Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH3)2Cl12, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et al. (Nature, 1965, 205, 698; Nature, 1972, 222, 385).
The physician's Desk Reference (PDR) reports that cisplatin (the commercial name is Platinol.RTM.) can be used to treat testicular cancer, ovarian cancer, and bladder cancer.
Rosenberg et al., U.S. Pat. No. 4,177,263, describes methods of treating cancer using cisplatin and cisplatin analogs. The compounds were effective for treating leukemia and tumors induced in mice.
Chemical & Engineering News (Oct. 23, 1995) reported that "[Cisplatin] was first synthesized in the 1800s, but its anticancer activity was not discovered until the 1960s. In 1979, it was approved by the Food & Drug Administration for clinical treatment of testicular and ovarian tumors and cancers of the head and neck. Cisplatin and an analog, carboplatin, are now among the most widely used anticancer drugs."
After so many years, cisplatin is still being widely used because of its efficacy. However, its major drawback, the toxicity, is still a major concern.
Many attempts have been made to modify the cisplatin molecule in order to reduce its toxicity. Other attempts have been made to understand the interaction between cisplatin and DNA, which is the ultimate target of cisplatin. A few attempts have also been made to modify the composition of cisplatin dosage form to reduce its toxicity or improve its efficacy.
Many articles have been published which suggest modifying the composition of the dosage forms of cisplatin by combining it with other compounds. For example, cisplatin has been used in combination with caffeine by H. Yasutake et al. (Gan to Kagaku Ryoho 1989, 16, 2031-8) and by H. Tsuchiya (Kanazawa Daigaku Juzen Igakkai Zasshi 1988, 97, 543-56). Cisplatin has also been used in combination with cytosine arabinoside and the combination has shown some advantages as shown by J. Berek et al. (Obstet. Gynecol. 1989, 74, 663-6). Another combination, cisplatin and novobiocin, has also been shown to be advantageous by P. Eder et al. (Cancer Research 1989, 49 595-8, U.S. Pat. No. 5,130,145). This prior art indicates that when cisplatin and L-ascorbic acid are administered simultaneously, the anti-tumor activity is higher.
None of these prior arts suggest or disclose using folic acid along with cisplatin in a pharmaceutical composition for cancer therapy. This may be because folic acid has not been used as a conventional pharmaceutical excipient.